Orally applicable contrast agents for cholecystography

ABSTRACT

COMPOUNDS OF THE FORMULA   -CO-)-BENZENE   WHEREIN R1 IS METHYL OR ETHYL WHEN R2 IS HYDROGEN, OR R1 AND R2 JOINTLY ARE ETHYLENEOXYETHYLENE, AND R3 IS METHYL OR ETHYL, AND THEIR PHYSIOLOGICALLY TOLERATED ALKALI METAL, ALKALINE EARTH METAL, AND ALKANOLAMINE SALTS PRODUCE SUPERIOR X-RAY IMAGES OF THE GALL BLADDER AND OF THE BILE DUCTS AFTER ORAL INGESTION AND ARE WELL TOLERATED AND QUICKLY ELIMINATED IN EFFECTIVE DOSES. 1,3,5-TRI(I-),2-(HOOC-CH(-R3)-CH2-O-CH2-CH2-),4-(R1-N(-R2)

United States Patent 3 825 591 ORALLY APPLICAIBLE CONTRAST AGENTS FORCHOLECYSTOGRAPHY Ernst Felder and Davide Pitre, Milan, Italy, assignorsto Bracco Industria Chimica Societe per Azioni, Milan,

Italy No Drawing. Filed June 1, 1972, Ser. No. 258,777 Claims priority,application 7S/v;i1tzerland, June 23, 1971,

Int. Cl. C07c 101/72 US. Cl. 260-519 4 Claims ABSTRACT OF THE DISCLOSURECompounds of the formula wherein R is methyl or ethyl when R ishydrogen, or R and R jointly are ethyleneoxyethylene, and R is methyl orethyl, and their physiologically tolerated alkali metal, alkaline earthmetal, and alkanolamine salts produce superior X-ray images of the gallbladder and of the bile ducts after oral ingestion and are welltolerated and quickly eliminated in effective doses.

This invention relates to iodine-bearing X-ray contrast agents, andparticularly to compounds and compositions which preferentially make thegall bladder and bile ducts radiopaque after oral ingestion.

Because of the hazards inherent in the intravenous administration oforganic iodine compounds prior to cholecystography, which hazards arenot readily dealt with outside of a Well-equipped hospital, privatepractitioners prefer to prepare patients for cholecystography with oralmedication. The radiopaque compounds and compositions availableheretofore for this purpose are not entirely satisfactory, particularlywhen it is important to visualize the bile ducts.

It has now been found that compound of the formula l C O and theirphysiologically tolerated salts with metals and amines, particularlyalkali metals, alkaline earth metals, and alkanolamines comparefavorably with the best cliniclly tested, orally administered contrastmedia for cholecystography in their toxicity and their ability of makingthe gall bladder visible, and are superior to the known contrast mediasuitable for oral ingestion in preferentially accumulating in the gallbladder and there-by reliably producing X-ray images of the bile ductswhen R in the formula is methyl or ethyl, R being hydrogen, or R and Rjointly are ethyleneoxyethylene in a morpholine ring, and R is methyl orethyl. Under otherwise identical conditions, the compounds in which R isethyl are preferred over those in which R is methyl.

In the following Table, pertinent data on four compounds A to D of theinvention are compared with corresponding data obtained under closelycontrolled identical conditions on eight compounds E to M. Compounds E,F, G, and H are similar to the compounds of the invention in theirchemical structure, the rather different compounds I and K arerepresentative of the most favorable combination of features found inorally administered cholecystographic agents in current clinical use,and compounds L and M are homologs of compounds A and C respectively.The compounds identified by letters A to M are:

A: 3- [2- 3-N-ethylcarbamoyl-Z,4,6-triiodophenoxy ethoxy]-2-ethylpropionic acid B: 3- [2-3-N-methylqarbamoyl-2,4,6-triiodophenoxy ethoxy]-2-ethylpropionic acidC: 3- [2- 3-N-methylcarbamoyl-2,4,6-triiodophenoxy)ethoxy]-2-methylpropionic acid D: 3- 2-3-N-morpholino-oarbonyl-2,4,6-triiodophenoxy)-ethoxy]-2-methylpropionicacid E: 3-N-morpholino-carbonyl-2,4,6-triiodophenoxybutyric acid (US.Pat. N0. 3,452,134)

F: 2- 3-N-propylcarbamoyl-2,4,6-triiodophenoxy butyric acid (East GermanPat. No. 48,210)

G: 2- [2-( 3-N-ethylacetylamino-2,4,6-triiodophenoxy ethoxy]propionicacid (Swiss Pat. No. 483,262)

H: 2- 2- 3-acetylamino-2,4,6-triiodopl1enoxy) -ethoxy] propionic acid I:3-(3-amino-2,4,6-triiodophenyl)-2-ethylpropionic acid (iodopanoic acid)K: 3-(3-dimethylaminomethylenamino-2,4,6-triiodophenyl)-propionic acid(iopodate) L: 2- [2- 3-N-ethylcarbamoyl-2,4,6-triiodophenoxy)ethoxyJbutyric acid M: 2- 2- 3-N-methylcarbamoyl-2,4,6-triiodophenoxy)ethoxyJpropionic acid The toxicity values in the Table are LD inmg./-kg. mouse and were determined by oral ingestion and by intravenousinjection (i.v.), the latter method being considered more reliablebecause it is not affected by variations in resorption through theintestinal wall.

The cholecystographic properties of the compounds were determined by themethod of J. O. Hoppe (J. Amer. Pharm. Assoc., Sci. Ed. 48, 368-379,1959) and were evaluated in the Hoppe Index scale on which 0 indicatesno X-ray image, 1 a weak, 2 an adequate, 3 a good, and and 4 anexcellent opacity and contrast quality of the image.

The visibility of the bile ducts is indicated in the Table on anarbitrary, but reproducible scale on which indicates no image or only anoccasion image, indicates visibility in all instances, and indicates animage of superior detail.

The cholecystographic tests were performed on dogs (1) or on cats (2) ata dosage rate (a) of mg./kg. body weight or (b) of 200 mg./kg. bodyweight, all test compounds being administered orally. Hoppe Index valueswere determined 2, 4, 6, 8, and 24 hours after ingestion.

20% Suspensions of the free acids were prepared with gum arabic and wereadministered to the test animals by means of a stomach tube in thedetermination of Hoppes Index and of oral toxicity. Salts with sodium orN-methylglucamine, which are physiologically equivalent, were employedin determining toxicity by intravenous injection.

TABLE Toxicity Animal Hoppe Index after- Bn e Compound Oral LV. Dosage2hrs. 4hrs. fihrs. 8hrs. 24 hrs. ducts A 2,800 1,400 llb 2.5 3.5 3.5 2/b2 3 a B 1,400 lla 1 2 2 2 llb 1 2 2.5 2/a 2 2 3 2/b 2 2.5 a

C 4,000+ 1,050 Ill) 2 2 2.5 3 2/b 2.5 3.5 3.5

D 3,700 550 lla 2.5 3 3 3 llb 0.5 s 4 a5 2/b 2.5 3.5 3.5

F -1..- 5,000 1,100 l/a 1.5 2 2 2 1/b 1 2 2 2 425 1/a 1 2.25 2.75 llb 2.75 3 3.25 2. 75

1,480 l/a 0 0 0.25 0.25 0 1/b 0 0.5 0.5 0.5 0

24o llb 1.5 1.5 2 0.5

2,100 1/a 0 0 0 0 Ill: 0 0 0 0 0 Nora-The toxicity values for Compound Dare only approximate. Compound L left Compound M produced oligouria.

As is evident from the Table, the compounds of the invention aresignificantly better tolerated than Compounds I and K which are now inWide clinical use. Their Hoppe Index values are better than or at leastas good as those of all other tested compounds, and they are unique intheir ability of precisely and reliably visualizing the bile ducts in amanner not possible heretofore except after intravenous injection of thecontrast agents.

Because of their low toxicities, the compounds of the invention may beemployed at higher dosage rates than conventional X-ray contrast agentswhich are administered orally. Because of the rapid excreation of thecontrast agents of this invention and because of the absence of residuesin the intestine, frequently observed with known orally appliedradiopaque materials, such higher dosage rates are permissible with thecompounds of the invention without causing disturbing side effects.

Many advantages of the invention apparently are due to the3-oxy-2-alkylpropionic acid radicals present in all the compounds of theinvention. It will be noted from the Hoppe Index values in the Tablethat Compounds L and M have little or no value in producing an X-rayimage of the gall bladder whereas their next adjacent homologs,Compounds A and C, are among the best examples of this invention.

The compounds of the invention may be employed in the form of the freecarboxylic acids or as salts with metals and amines which arephysiologically tolerated when orally administered in amounts suificientfor cholecystography. The alkali metal salts, such as the sodium andlithium salts, the alkaline earth metal salts, particularly themagnesium and calcium salts, and salts of alkanolamines are preferred.Suitable alkanolamines include N- methylglucamine, N-methylxylamine(l-methylamino-ldesoxy- [D] -xylite) 1-methylamino-2, 3-propanediol,ethanolamine, and diethanolamine. Other suitable alkanolamines willreadily suggest themselves to the pharmaceutical chemist. The free acidsand their salts may be compounded individually or as mixtures inradiopaque compositions.

The compounds of the invention may be prepared by reacting a3-carbamoyl-2,4,6-triiodophenol of the formula with a reactivederivative of 3-alkoxy-Z-alkylpropionic acid of the formula nol may beemployed in the form of the corresponding alkali metal phenolate. Thepreferred reactive derivatives are the 3-haloethoxy-Z-alkylpropionicacid esters and the 3-alkylsulfonyloxy-or3-arylsulfonyloxyethoxy-2-alkylpropionic acid esters, and thecondensation products are saponified after ether formation to obtain thefree acid or the salt to be employed as an X-ray contrast agent.

The following Examples are further representative of the methods ofpreparing and using the compounds of this invention.

EXAMPLE 1 27.5 g. Sodium 3-N-methylcarbamoyl-2,4,6 triiodophenolate(0.05 mole) was dissolved in 50 ml. dimethylformamide, and 16.5 g.3-(2-iodoethoxy)-2-ethylpropionic acid ethyl ester (0.055 mole) wasadded with stirring at 70 C. over a period of to 20 minutes. Thereaction mixture was heated to NW C., and stirring was continued for 16hours at that temperature. The mixture was then cooled to ambienttemperature and poured into 500 ml. water. An oily product precipitatedand gradually solidified. It was separated from the supernatant liquidand dissolved in ethyl acetate. The solution was washed sequentiallywith water, sodium carbonate solution, water, sodium hydrogen sul fitesolution, and again with water, dried over desiccated sodium sulfate,and evaporated to dryness. The crystalline residue Was suspended inisopropyl ether, filtered oil with suction, and washed with isopropylether. IIt weighed 27.45 g. (78.5% yield), melted at 8-889 C., and gavean R value of 0.70 in a thin layer chromatogram on silica gel withbenzene/chloroform/glacial acetic acid 7:3:2. It was identified as theethyl ester of Compound B by elementary analysis:

Calculated for C17H22I3NO5: -29. 12% c; 54.31% I Found: 29.27% C; 54.55%I 36 g. Ethyl ester prepared as described above was dissolved in 140 ml.ethanol, and 170 ml. 0.3 N sodium hydroxide solution was added graduallywith stirring at 50 C. over a period of three hours to saponify theester. The ethanol was distilled 01f in a vacuum, and the residue wasdiluted with water and extracted with ethyl acetate. The aqueous phasewas exposed to a vacuum to remove traces of dissolved ethyl acetate andacidified with 18% hydrochloric acid to precipitate Compound B in anamount of 26.9 g. (78% yield). It melted at 77-7 8 C.

After being suspended in 40 ml. boiling ethyl acetate, it was convertedto the more stable crystal form melting at 138 C., and having an R;value of 0.65 in a thin layer chromatogram prepared by means of theabove solvent system. It was identified by its elementary analysis:

Calculated for C H 'I NO 26.77% C; 56.57% I Found: 26.77% C; 56.31% IThe free acid is practically insoluble in water, soluble in the loweralkanols, readily soluble in aqueous solutions of bases such as sodiumhydroxide, ethanolamine, N-methylglucamine, etc. from which thecorresponding salts can be recovered by evaporation of the water or byother conventional methods.

The 3-'(.2-iodoethoxy)-2-ethylpropionic acid ethylester employed as astarting material was prepared as follows:

0.8 Mole ethylmalonic acid diethyl ester was reacted in ethyl ether with0.84 mole sodium hydride and thereafter with 0.8 mole'2-chloroethoxy-methyl chloride, and the2-(2-chloroethoxymethyl)-2-ethylmalonic acid diethyl ester wasrecovered. B.P. 136144 C. at 4 mm. Hg. 0.47 Mole of the diestcr werepartially saponified in 500 ml. 60% aqueous methanol with 0.5 molesodium hydroxide at '6065 C. in two hours. The methanol Was thenevaporated, and the residue was acidified and extracted with ethyl etherto recover 2-(2-chloroethoxymethyl)-2- ethylmalonic acid monoethyl esterwhich was decarboxylated by heating at 140-150 C. The resulting 3-(2-chloroethoxy)-2-ethylpropionic acid ethyl ester boiled at 11'91M C. at14 mm. Hg. 0.325 Mole of the lastmentioned ester was reacted with 0.65mole sodium iodide in 300 ml. ethanol by refluxing for -16 hours,whereupon the 3-(2-iodoethoxy)-2-ethylpropionic acid ethyl ester wasrecovered. B.P. 125-1128 C. at 3-4 mm. Hg n ='1.482.

EXAMPLE 2 11.3 g. Sodium 3-N ethylcar-bamoyl 2,4,6 triiodophenolate (thesodium salt of 3-hydroxy-2,4,6-triiodo- N-ethylbenzamide, 0.02 mole) Wasdissolved in 200 ml. dimethylformamide, and the solution was heated at90 C. for 15 hours with 6.6 g. 3--(2-iodoethoxy)-2-ethylpropionic acidethyl ester (0.022 mole). The ethyl ester of Compound A was obtained inan amount of "10.5 g. (73.5% yield) and melted at -8 2 C. whenrecrystallized from aqueous ethanol. The same result was achieved byusing 4.6 g. of the less costly 3-(2-chloroethoxy)-2- ethylpropionicacid ethyl ester with 3-4 g. sodium iodide.

The thin layer chromatogram of the ester on silica gel gave an R valueof 0.65 with chloroform/ glacial acetic acid 19:1. The compound wasidentified by elementary analysis:

Calculated for C H 1 'NO 30.23% C; 53.24% I Found: 30.04% C; 53.01% IThe ester was saponified as in Example 1 to produce the free acid in ayield of 52%. When recrystallized from ethyl acetate, Compound A meltedat 1'1'4 1l6 C.-

and gave an R value of 0.415 in a thin layer chromatogram on silica gel(ethyl acetateisopropanol/conc. ammonium hydroxide 55 :35 :20). It wasidentified by elementary analysis:

Calculated for C H I NO 27.97% C; 55.42% I Found: 27.89% C; 55.52% 1Compound A is practically insoluble in water, but soluble in the loweralkanols and in the aqueous bases mentioned in Example 1.

EXAMPLE 3 22 g. 3-N-Methylcarbamoyl-2,4,6-triiodophenol sodium salt wasdissolved in 40 ml. dimethylformamide. 7.9 g.3-(2-Chloroethoxy)-2-methy1propionic acid methyl ester was added, andthe mixture was stirred at C. for 20 hours to form the methyl ester ofCompound C. When recrystallized from a small amount of ethyl acetate,the ester melted at 7475 C. and had an R value of 0.56 in a thin layerchromatogram on silica gel (chloroform/ glacial acetic acid 19:?1).

Calculated for C H -I NO 26.77% C; 56.57% I Found: 26.73% C; 56.43% IThe ester was saponified in the manner of Example 1 to Compound C with ayield of 75.5%. The free acid melted at 1-10112 C. R =0.-26(chloroform/glacial acetic acid 19:1).

Calculated for C H I NO 25.51% C; 57.77% I Found: 25.47% C; 57.73% I Thefree acid is practically insoluble in Water, soluble in 10 parts (byweight) cold ethanol or 2 parts boiling ethanol, in 50 parts coldchloroform or 10 parts boiling chloroform. The solubility in water at 20is 50 g./ 100 ml. for the sodium salt and for the N-mehylglucamine salt.

The 3-(2-chloroethoxy)-2-methylpropionic acid methyl ester employed as astarting material is prepared in a manner analogous to the preparationof the homologus ethyl ester described in Example 1.

g. Methylmalonic acid diethyl ester was reacted with 20 g. sodiumhydride and 103.2 g. 2-chloroethoxymethyl chloride to 118.7 g.2-(2-chloroethoxymethyl)-2- methylmalonic acid diethyl ester boiling at132139 C./ 4 mm. Hg. The ester was saponified with 42 g. sodiumhydroxide to 2-(2-chloroethoxymethyl) 2 methylmalonic acid which waspartly decarboxylated to form 3-(2- chloroethoxy)-2-methylpropionicacid. The free acid was converted by means of diazomethane to thedesired methyl ester which boiled at 103 105 C./ 16 mm. Hg.

EXAMPLE 4 13.4 g. Sodium 3-N-ethylcarbamoyl-2,4,6-triiodophenolate wasdissolved in 30 ml. dimethylformamide and reacted with 7.65 g.3-(2-iodoethoxy)-2-methylpropionic acid ethyl ester or with 5.16 g.3-(2-chloroethoxy)-2-methylpropionic acid ethyl ester in the presence of4.5 g. so-

7 dium iodide in hours at 90 C. to the ethyl ester of 3-[2-(3-N-ethylcarbamoyl-2,4,6-triiodophenoxy) ethoxy]- 2-methylpropionicacid ethyl ester melting at 99100 C. Thin layer chromatogram on silicagel with chloroform/ glacial acetic acid 19:1 R =O.69.

Calculated for C H I NO 29.12% C; 54.31% I Found: 29.17% C; 54.33% I Thefree acid was obtained in a yield of 89% by saponifying the ester withsodium hydroxide in ethanol and by acidfying the resulting solution ofthe sodium salt. It melted at 142143 C. Thin layer chromatogram onsilica gel with ethyl acetate/isopropanol/conc. ammonium hydroxidesolution 55:35:20. R =0.41.

The acid is practically insoluble in water, but dissolves readily inaqueous solutions of the afore-mentioned bases to form the correspondingsalts which were readily obtained in solid form by evaporating thesolutions in a vacuum.

The 3-(2-iodoethoxy)-2-methylpropionic acid ethyl ester employed as astarting material was prepared as follows:

267 g. 2-(2-Chloroethoxymethyl)-2-methylmalonic acid diethyl ester waspartially saponified to the monoethyl ester by means of 42 g. sodiumhydroxide. The monoester was decarboxylated to the3-(2-chloroethoxy)-2-rnethylpropionic acid ethyl ester (B.P. 102103C./l4 mm. Hg). The last-mentioned compound was reacted in an amount of93 g. with 144 g. sodium iodide to produce 98 g.3-(2-iodoethoxy)-2-methylpr0pionic acid ethyl ester (B.P. 119 C. at 3-5mm. Hg).

EXAMPLE 5 30.15 g. 3-N-Morpholino-carbonyl 2,4,6-triiodophenol sodiumsalt was dissolved in 50 ml. dimethylformamide and heated for hours at110 C. with 9.9 g. 3-(2-chloroethoxy)-2-methylpropionic acid mehyl esterto produce the methyl ester of Compound D which was saponified to 28.7g. of the free acid as described in Example 1.

The crude acid was dissolved in isopropanol containing 4 ml.cyclohexylamine, whereby the cyclohexylamine salt of Compound D wasgradually precipitated. The mixture was left standing overnight, and wasthen filtered with suction. The salt on the filter was washed withisopropanol and was then dissolved in about 300 ml. warm water. Thesolution was gradually stirred into 3% hydrochloric acid, whereby pureCompound D was precipitated. It was recovered in an amount of 23.9 g.(66.7% yield) and melted at 7578 C. Thin layer chromatogram on silicagel with chloroform/ glacial acetic acid 19:1: R =0.51.

Calculated for C17H2QI3NOG: I Found: 28.54% C; 53.22% I The free acid ispractically insoluble in water, but dissolves readily in methanol,ethanol, or chloroform. The sodium and N-mehylglucamine salts dissolvein approximately equal weights of water at 20 C.

3 [2 (3 Nmorpholinocarbonyl-2,4,6-triiodophenoxy)-ethoxy]-2-ethylpropionic acidwas prepared in an analogous manner.

The synthesis methods outlined above start with the methyl or ethylesters of the 3-(2-haloethoxy)-2-methylor 2-ehylpropionic acids whichare reacted with alkali metal triiodophenolates, but the same resultswere obtained by using the other lower alkyl esters, more specificallythe propyl, isopropyl, and butyl esters, and there is no reason toassume that other alkyl esters, less readily available, would not beequally operative.

The 3-(2-alkylor -arylsulfonyloxyethoxy)-2-methylor -ethylpropionic acidesters generally give better yields than the analogous3-(2-haloethoxy)-2-methylor -ethylpropionic acid alkyl esters, thehighest yields being generally produced by means of the3-(2-benzenesulfonyloxyethoxy)-2-ethylpropionic acid ethyl ester.

The condensation reactions may also be performed in ethanol,methoxyethanol, methylethylketone and other alochols and ketones inwhich the alkali metal phenolates are not readily soluble. The phenolsare reacted in the alcohls in the presence of an alkali metal alcoholatecorresponding to the alcohol employed as a solvent medium (for example,NaO-C H and NaOC H OCH with the afore-mentioned alcohols). An alkalimetal carbonate, such as potassium carbonate, is preferably employed asa basic condensation agent when the solvent is a ketone.

The compounds of the invention are compounded with excipient in themanner conventional in galenic pharmacy for convenient oraladministration. The free acids and the metal or amine salts may becombined with suitable carriers, diluents, coatings, or ingestiblecontainers to produce dosage units which are capsules, granulates,tablets, drages, globuli, suspensions or solutions. The liquidcompositions may also be administered rectally, but oral administrationis preferred. The compounds of the invention are perferably micronizedbefore being combined with other solid ingredients transparent toX-rays. Quicker absorption and denser shadows are normally obtained bythe micronized compounds than by other forms, while no intestinalresidues interfering with observation of the gall bladder or the bileducts are formed.

The following additional Examples illustrate methods of combining thecompounds of the invention with inert ingredients for convenient oraladministration, but these procedures, conventional in themselves, willreadily be modified by a skilled pharmacist to satisfy particularrequirements.

EXAMPLE 6 Compound A was micronized to a particle size of less than 4 2,and the fine powder was mixed intimately with 20.4 g. Pluronic F68, asurface active material obtained by subjecting polypropyleneglycol tocondensation with ethylene oxide, which is a solid at normal ambienttemperature and prevents aggregation of the fine particles. The mixturewas driven through a stainless steel screen having 324 openings persquare centimeter, and 20.4 g. microcrystalline starch were admixed.

The resulting mixture was moistened with enough distilled water topermit the mass to be granulated by passage through a screen having 56openings per square centimeter. The granulate was dried in an air streamat 40 C., mixed with 7.2 g. magnesium stearate as a lubricant, anddistributed uniformly in 600 soft gelatin capsules containing each 500mg. of the active compound.

EXAMPLE 7 3 kg. Compound B was kneaded mechanically into a dough-likemass with 2 liters starch paste containing g. corn starch. When themoist mass was tacky, a little dry starch was added. The mixture wasthen granulated on a granulating dish, and the granulate was dried in avacuum. The dry granules were further mixed with 0.5 kg. corn starch and25 g. magnesium stearate, and compressed to tablets containing each 500mg. of the active ingredient.

EXAMPLE 8 The sodium salt of Compound D in an amount of 5 kg. was mixedintimately with 0.75 kg. granulated sugar, and 0.75 kg. corn starch. Themixture was moistened with one liter 50% aqueous ethanol and thengranulated. The granulate was dried, screened, mixed with 0.65 kg. cornstarch, 0.05 kg. talcum, and 0.05 kg. magnesium stearate and pressed tomake 10,000 tablets.

EXAMPLE 9 Granules containing Compound A as the active ingredient wereprepared as described in Example 1. They were coated in a kettle withsugar syrup in a weight ratio of 3:1, and the pills so formed were waxedwhan dry.

9 10 What is claimed is: 3. A compound as set forth in claim 1, whereinR is '1. A compound which is an acid of the formula ethyl.

I 4. A compound as set forth in claim 3, which is a carboxylic acid. 5References Cited 1;, UNITED STATES PATENTS I I 3,452,134 6/1969 Tilly260-519 I 3,553,259 1/1971 Felder et al. 260-619 A 1o FOREIGN PATENTS ora salt of said acid with a metal or an amine, said salt 772,035 2/1972Belgium 2605 19 being physiologically tolerated when administered orallyin an amount suflicient for cholecystography, in said for- LORRAINEWEINBERGER Pnmary Exammer mula R being methyl or ethyl, R beinghydrogen, R 15 P. J. HAGAN, Assistant Examiner being methyl or ethyl. 1

2. A compound as set forth in claim 1, wherein said US. Cl. X.R. metalis an alkali metal, calcium, OI magnesium, and said 2 0 247 2 R 501 11.424 5 amine is an alkanolamine.

